Defining the Role of of Noncanonical GPCR Signalling in Pulmonary Hypertension
定义非典型 GPCR 信号在肺动脉高压中的作用
基本信息
- 批准号:10544136
- 负责人:
- 金额:$ 3.77万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-05-01 至 2024-04-30
- 项目状态:已结题
- 来源:
- 关键词:Angiotensin II ReceptorArrestinsBiochemicalBiological AssayBiotinCardiovascular systemCell LineCell physiologyComplexCouplingDevelopmentDiseaseDrug TargetingDrug usageEndosomesEndothelial CellsEndotheliumEngineeringEventExtracellular Signal Regulated KinasesFDA approvedG Protein-Coupled Receptor SignalingG-Protein-Coupled ReceptorsGTP-Binding ProteinsGenomeGoalsHarvestHealthHeterotrimeric GTP-Binding ProteinsImpairmentKnowledgeLabelLigandsMedicalMissionMutatePathway interactionsPatientsPeroxidasesPharmaceutical PreparationsPharmacologyPhysiologicalPhysiologyPlayProteinsPulmonary HypertensionReceptor, Angiotensin, Type 1ResearchRoleScientistSignal PathwaySignal TransductionSystemTestingTherapeuticTrainingTubeUnited States National Institutes of HealthVariantVascular remodelingWorkascorbatebasechemokine receptordesensitizationendothelial dysfunctioninsightmigrationnanoluciferasenovelnovel therapeuticspreferencepublic health relevancepulmonary artery endothelial cellpulmonary vascular disorderreceptorreceptor functionreceptor internalizationright ventricular failuretooltraffickingvasoconstriction
项目摘要
ABSTRACT
Pulmonary hypertension (PH) is characterized by endothelial dysfunction, irregular vascular remodeling and
consistent vasoconstriction leading to eventual fatal right heart failure despite current medical therapies. The
most common drug targets in PH are G protein coupled receptors (GPCRs), which are a target for almost a
third of all FDA-approved drugs. Although these receptors have been studied intensely for over 40 years,
several aspects of GPCR signaling remain poorly understood. Canonically, it has been well established that
these receptors are able to signal through both heterotrimeric G proteins and β-arrestins (βarrs). These events
were thought to be largely separable given that G proteins primarily initiate downstream signaling while βarrs
can signal and regulate receptor desensitization and trafficking. Recent studies have suggested evidence
for a combined role of G protein and βarr in GPCRs signaling through the formation of signaling
“megaplexes” and the impairment of βarr-based signaling in the absence of functional G proteins. However,
there remains a significant knowledge gap surrounding the significance of G protein and βarr coordinated
signaling. Our long term aim is to understand the signaling mechanisms of GPCRs to provide better insight for
the development of novel therapeutics for PH. In our recent studies, we have directly assessed whether G
proteins and βarrs can interact across a panel receptors and were surprised to find that all receptors tested
could form a complex between the inhibitory G protein (Gαi) and βarr, including the type 1 angiotensin II
receptor (AT1R) and atypical chemokine receptor 3 (ACKR3, also known as CXCR7), which are both potential
drug targets in PH. We further found that these complexes could interact with secondary effectors, most
notably extracellular signal-regulated kinase (ERK). These results suggested a conserved, non-canonical
role for Gαi:βarr signaling across GPCRs. Our overarching goal is to define the mechanism in which
Gαi:βarr form complexes and understand their impact on physiology. We hypothesize that Gαi:βarr complex
formation require a discrete set of motifs present in Gαi, βarrs and GPCRs and that these complexes regulate
endothelial function in PH. To test this hypothesis, first I will determine the specific sequence motifs in Gαi, βarr
and the receptor that are required to form Gαi:βarr complex. Second, I will determine the signalling pathways
that are regulated by Gαi:βarr interaction using APEX proximity labeling and novel “complex BRET” assays.
Third, I will determine the impact of Gai:βarr within PH patient endothelial cells by targeting Gαi and βarr
signaling and testing their effects on endothelial function. This study strives to understand an emerging
paradigm in GPCR signalling in which Gαi and βarr work together to orchestrate unique downstream signalling.
Completion of these aims will provide novel insights for cell signalling, development of new pharmacological
tools targeting Gαi:βarr coupling, and lay the groundwork for therapeutics for cardiovascular-related diseases.
These studies will also provide an excellent opportunity for my training to develop as an independent scientist.
摘要
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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- DOI:
10.1182/blood-2024-210030 - 发表时间:
2024-11-05 - 期刊:
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- 作者:
Claudia Y Lee;Grig Zhang;Chris Y Coker;Sisi Zheng - 通讯作者:
Sisi Zheng
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{{ truncateString('Claudia Y Lee', 18)}}的其他基金
Defining the Role of of Noncanonical GPCR Signalling in Pulmonary Hypertension
定义非典型 GPCR 信号在肺动脉高压中的作用
- 批准号:
10669247 - 财政年份:2021
- 资助金额:
$ 3.77万 - 项目类别:
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